From Development To Manufacturing: A More Controlled Approach To Chromatography Scale-Up

By Anilkumar Kangokar and Dr. Kathleen Mihlbachler, Repligen

Moving chromatography processes from development to manufacturing can reveal variability that is difficult to anticipate at smaller scales. Differences in column dimensions, pumps, valves, flow paths, holdup volumes, and feed or buffer composition can alter flow delivery, gradient formation, and overall process performance, even when the process recipe remains unchanged. To reduce the risk of breakthrough or other deviations, manufacturers may build additional operating margin into the process or deliberately underload columns. These approaches can protect performance but may also reduce resin utilization, increase cycle numbers and buffer consumption, extend processing times, and limit manufacturing capacity.

Stronger process control begins with understanding and managing these sources of variability during development. Design of experiments can help identify the effects of equipment and process variables, while system-level engineering can make critical operating characteristics more reproducible across scales. Precise, pressure-independent flow control is particularly important for maintaining intended conditions during chromatography, while accurate conductivity measurement helps ensure consistent buffer delivery. Integrated process analytical technology can further distinguish simple monitoring from active control by providing real-time information that supports process decisions, enabling greater consistency from development through manufacturing.